Pivotal Trials Lead to Transformative Approaches in HER2+ Breast Cancer

December 2, 2020 - Four pivotal trials––KATHERINE, FeDeriCa, DESTINY-Breast01, and HER2CLIMB have not only amplified the armamentarium in HER2-positive breast cancer, but have illustrated the importance of neoadjuvant therapy, alternative administration methods, high-potency HER2-targeted therapy, and inclusion of all-comers with brain metastases in clinical trials.

Four pivotal trials––KATHERINE, FeDeriCa, DESTINY-Breast01, and HER2CLIMB have not only amplified the armamentarium in HER2-positive breast cancer, but have illustrated the importance of neoadjuvant therapy, alternative administration methods, high-potency HER2-targeted therapy, and inclusion of all-comers with brain metastases in clinical trials.

In a presentation during the 2020 Institutional Perspectives in Cancer webinar on breast cancer, Paula Pohlmann, MD, MSc, PhD, a medical oncologist at Georgetown Lombardi Comprehensive Cancer Center, MedStar Health, shed light on the key findings from each trial.


The phase 3 KATHERINE study evaluated the role of adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with residual disease in the breast or axillary lymph nodes. Eligible patients were randomized 1:1 within 12 weeks of surgery to 3.6 mg/kg of intravenous (IV) T-DM1 every 3 weeks for 14 cycles (n = 743) or 6 mg/kg of IV trastuzumab (Herceptin) every 3 weeks for 14 cycles (n = 743). Radiation and endocrine therapy were given with HER2-targeted therapy if indicated.

Invasive disease-free survival (DFS) served as the primary end point. The 3-year iDFS rate was 88.3% with T-DM1 vs 77.0% with trastuzumab, representing a 50% reduction in the risk of invasive disease or death (HR, 0.50; 95% CI, 0.39-0.64; P < .0001). Homogenous benefit was seen in a subgroup analysis, and was irrespective of clinical presentation, hormone receptor status, pathological nodal status post neoadjuvant therapy, single vs dual anti-HER2 therapy in the neoadjuvant setting, and volume of residual disease after neoadjuvant therapy.1

A biomarker analysis of post-neoadjuvant treatment samples that was presented at the 2020 ASCO Virtual Scientific Program indicated that patients with HER2 expression, (≤median, HR, 0.58; >median, HR, 0.30), PD-L1 expression (≤median, HR, 0.31; >median, HR, 0.49), CD8 expression (≤median, HR, 0.32; >median, HR, 0.40), and T-effector signature (≤median, HR, 0.33; >median, HR, 0.45) derived greater benefit with T-DM1 vs trastuzumab regardless of expression level. Additionally, PIK3CA mutation status did not influence outcomes (HR, 1.04; 95% CI, 0.78-1.38).2

Surgical samples had lower HER2 mRNA expression vs pre-neoadjuvant samples. High HER2 mRNA expression and low PD-L1 expression conferred a worse outcome with trastuzumab but not with T-DM1. No distinct association between T-effector signature and outcome was found in either treatment arm. 

Regarding safety, T-DM1 led to higher rates of any-grade and grade 3 or greater adverse effects (AEs) vs trastuzumab (98.8% vs 93.3%; 25.7% vs 15.4%). In particular, Pohlmann highlighted the higher rates of peripheral sensory neuropathy (18.6% vs 6.9%), elevated aspartate aminotransferase (28.0% vs 5.6%), thrombocytopenia (5.7% vs 0.3%), and AEs leading to drug discontinuation (18.0% vs 2.1%) with T-DM1 vs trastuzumab, respectively. 

In May 2019, the FDA approved T-DM1 for use as adjuvant therapy in women with HER2-positive early breast cancer with residual disease after neoadjuvant trastuzumab and chemotherapy.

“[Now that we know] adjuvant T-DM1 in patients with HER2-positive residual breast cancer after neoadjuvant therapy and surgery improves iDFS compared with trastuzumab, [there has been a] strong push for neoadjuvant therapy for most patients with early-stage HER2-positive breast cancer,” explained Pohlmann.


The phase 3 FeDeriCa trial evaluated subcutaneous administration of the fixed-dose combination of pertuzumab (Perjeta) and trastuzumab in combination with chemotherapy (n = 250) vs IV pertuzumab and trastuzumab plus chemotherapy (n = 250) in patients with early-stage disease.

The primary end point was noninferiority of the predose cycle 8 pertuzumab serum Ctrough. With regard to the pertuzumab component of the fixed-dose combination, the mean value of predose cycle 8 serum Ctrough was 93.7 µg/mL vs 78.5 µg/mL for IV pertuzumab. Geometric means were 88.7 and 72.4 µg/mL, respectively (geometric mean ratio [GMR], 1.22; 90% CI, 1.14-1.31).3

For the trastuzumab component of the fixed-dose combination, the mean value of predose cycle 8 serum Ctrough was 62.9 µg/mL vs 48.1 µg/mL. Geometric means were 58.7 µg/mL for the subcutaneous formulation and 44.1 µg/mL for the IV formulation of trastuzumab (GMR 1.33; 90% CI, 1.24-1.43).

Additionally, the pathologic complete response (pCR) rates were comparable between arms, at 59.7% (95% CI, 53.3%-65.8%) in the subcutaneous arm vs 59.5% (95% CI, 53.2%-65.6%) in the IV arm.

Regarding safety, AEs were comparable between arms. Grade 3 or greater AEs occurred in 48.8% of patients in the subcutaneous arm vs 52.8% in the IV arm. Though, a higher rate of infusion-related reactions within 24 hours of administration occurred in the subcutaneous arm (17.3%) vs the IV arm (13.5%).

In June 2020, the FDA approved the fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase-zzxf (Phesgo) for administration via subcutaneous injection in combination with IV chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer.

“Overall, subcutaneous pertuzumab and trastuzumab with hyaluronidase-zzxf represents a new option of subcutaneous treatment for patients who are candidates for double anti-HER2 therapy with pertuzumab and trastuzumab,” explained Pohlmann, who added that the subcutaneous formulation has the added advantage of being delivered into the thigh over 5 to 8 minutes vs 30 to 60 minutes with IV pertuzumab and 30 to 90 minutes with IV trastuzumab.


The phase 2 trial evaluated the role of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with metastatic breast cancer previously treated with T-DM1 (n = 184).

Objective response rate (ORR) served as the primary end point of the study. Among the entire patient population, the ORR was 60.9% at a 5.4-mg/kg dose. Among patients who had received 2, 3, 4, 5, or 6 prior lines of therapy, the ORRs were 76.7%, 62.5%, 53.8%, 64.3%, and 55.3%, respectively. Moreover, the disease-control rate and median progression-free survival, which served as secondary end points of the study, was 97.3% and 16.4 months. The estimated 1-year overall survival (OS) rate was 86%.4

Nausea and neutropenia were the most common grade 3/4 AEs, occurring in 7% and 16% of patients, respectively. Additionally, fatal outcomes due to interstitial lung disease (ILD) occurred in 2.6% (n = 6) of patients.

In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting.

“Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer, but there is substantial risk of [ILD] that requires attention to pulmonary symptoms and careful monitoring,” said Pohlmann.


The phase 2 HER2CLIMB trial evaluated the addition of tucatinib (Tukysa) to trastuzumab and capecitabine (Xeloda) in patients with advanced HER2-positive breast cancer with and without brain metastases.

Eligible patients were randomized 2:1 to 300 mg of tucatinib twice daily during each 21-day cycle plus 1000 mg/m2 of capecitabine twice daily on days 1 to 14 of each 21-day cycle and 8 mg/kg of IV trastuzumab on day 1 of cycle 1, followed by 6 mg/kg thereafter on day 1 of each 21-day cycle (n = 410) or placebo plus the same schedule of trastuzumab and capecitabine (n = 202). 

Among the general population, the median PFS was 7.8 months with tucatinib vs 5.6 months with placebo (HR, 0.54; 95% CI, 0.42-0.71; P < .001).5 Among the CNS population, the median PFS was 9.9 months and 4.2 months, respectively (HR for CNS progression, 0.32; 95% CI, 0.22-0.48; P < .00001).6 The median OS was 21.9 months with tucatinib vs 17.4 months with placebo (HR, 0.66; 95% CI, 0.50-0.88; P = .0048). Among the CNS population, the median OS was 18.1 months vs 12.0 months, respectively.

In terms of safety, grade 3 or higher AEs occurred in 55.2% of patients in the tucatinib arm vs 48.7% of patients in the placebo arm. AEs leading to treatment discontinuation of tucatinib, placebo, and capecitabine occurred in 5.7%, 3.0%, and 9.8% of patients, respectively. Alanine aminotransferase/AST abnormalities were mostly low grade, transient, and reversible, said Pohlmann. Bilirubin elevations occurred in 18.6% with tucatinib vs 10.2% with placebo; however, elevations that were at least grade 3 occurred less often with tucatinib, at 0.7% vs 2.5% with placebo. Serum creatinine elevations occurred in 13.9% of patients in the tucatinib arm vs 1.5% in the placebo arm. 

In April 2020, the FDA approved tucatinib for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting.

“The tucatinib regimen is active for intracranial and extracranial disease in patients with HER2-positive metastatic breast cancer and [was shown to be] safe, with a low rate of treatment discontinuation due to [AEs],” said Pohlmann.


  1. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
  2. Denkert C, Lambertini C, Fasching PA, et al. Biomarker data from KATHERINE: a phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. J Clin Oncol. 2020;38(suppl 15):502. doi:10.1200/JCO.2020.38.15_suppl.502
  3. Tan AR, Im SA, Mattar A, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Can Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-PD4-07
  4. Modi S, Andre F, Krop I, et al. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. J Clin Oncol. 2020;38(suppl 15):1036. doi:10.1200/JCO.2020.38.15_suppl.1036
  5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
  6. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005